HL and LPL are key enzymes responsible for the hydrolysis triglyceride present in chylomicrons, VLDL and LDL. Patients with deficiency of either LPL or HL have marked derangements of normal triglyceride metabolism and present with either familial chylomicronemia or a pseudo Type III hyperlipoproteinemic phenotype. In order to gain insights into the underlying molecular mechanisms that lead to the phenotypic expression of these two syndromes we have characterized the genetic defects in patients with either LPL or HL deficiency. The proband with HL deficiency presented with hypertriglyceridemia, pancreatitis, CAD and had beta-VLDL in plasma as well as absent post- heparin HL activity. DNA sequencing of the HL gene identified a single A to G mutation in intron 1 located within a potential branch lariat signal, which generates an alternative splice site leading to the synthesis of a truncated, non-functional HL. Our studies establish the important of this sequence for normal splicing of HL MRNA and identify alternative splicing as a novel mechanism leading to enzyme deficiency of the lipolytic system. The LPL gene of two different patients presenting with classical features of familial chylomicronemia has been studied. Unlike all other patients with LPL deficiency their plasma triglycerides normalized after treatment with either omega-3-fatty acids (omega-3-FA) or medium chain triglyceride (MCT) oil. Although macrophage LPL MRNA levels and the specific activity of post heparin plasma LPL were normal, total LPL levels in post heparin plasma were reduced to less than 10 percent of normal. Sequence analysis of the patient's LPL gene revealed no structural, regulatory, or splice defects. Our studies identify a subset of patients with unique gene defects that lead to a functional deficiency of LPL and respond to dietary oil therapy by normalizing triglycerides and indicate that all patients presenting with LPL deficiency should be given a therapeutic trial of omega-3-FA or MCT oil.